4H-1,4-Benzothiazine derivatives

ABSTRACT

4H-1,4 benzothiazine derivatives having anorectic activity and their preparation including intermediate compounds are disclosed.

The present invention relates to 4H-1,4 benzothiazine derivatives andnovel intermediates used in the preparation thereof. More particularly,this invention provides chemical compounds of the formula ##STR1##wherein R and R' each represent hydrogen or lower alkyl containing 1 to4 carbon atoms; R2 and R3 represent hydrogen, halogen, nitro, amino, oralkoxy containing 1 to 4 carbon atoms; when R2 is other than alkoxy, R3represents hydrogen and when R2 is an alkoxy group, R3 is hydrogen orthe same alkoxy group; Z represents sulfur, sulfinyl or sulfonyl; Ar isphenyl, mono or di substituted phenyl, wherein the substituents may behalogen, hydroxy, trifluoromethyl, methoxy, cyano or lower alkyl having1 to 4 carbon atoms; and pharmaceutically acceptable acid addition saltsof the compounds of the above formula.

Among the substituents represented by R and R' hydrogen is preferred.However, R and/or R' may represent lower alkyl, methyl, ethyl, 1-methylethyl, or propyl (i.e., alkyl containing less than 4 carbon atoms).Positioning of the substituents on the phenyl relative to the point ofattachment of the phenyl, or where two are present, to each other is notcritical. Thus, within the scope of this invention are o-, m-, orp-monosubstituted phenyls of the type described above, such aso-fluorophenyl, o-chlorophenyl, m-trifluoromethylphenyl, p-bromophenyland p-hydroxyphenyl and 2, 4-, 2,6-, and 3,4-disubstituted phenyls ofthe type described above, such as 2,4-dichlorophenyl, 2,6-dichlorophenyland 3,4-dichlorophenyl. The preferred substituents of the substitutedphenyl representing Ar are halogens.

The intermediates of this invention are represented by formula II##STR2## wherein W is CN, CONH₂ or CON=CHNXY, wherein X, and Y, arelower alkyl having 1 to 4 carbon atoms; and R" represents hydrogen,methoxy, trifluoromethyl or lower alkyl having 1 to 4 carbon atoms whenR'" is hydrogen, and when R" is halogen, R'" is halogen or hydrogen.

Preferred acid addition salts of this invention are those which arepharmacologically acceptable, that is i.e., relatively non-toxic andeffective for the purposes set forth here and below.

Equivalent to the foregoing compounds, including salts, for the purposesof this invention are solvates thereof in which pharmacologicallyinsignificant amount of solvates are present.

The final product compounds to which this invention relate are usefulbecause of their valuable pharmacological properties. Thus, for example,they are anorectic. The anorectic activity of the instant compounds isevident from results of a test showing a dose responsive decrease infood intake and subsequent weight loss upon administration of thecompounds of the present invention. The procedure is as follows:

Male Sprague Dawley derived, COBS rats from Charles River BreedingLaboratories, (Portage, Mich.) weighed between 215 and 235 grams at thestart of the experiment. All the animals were housed in individual cagesand maintained on a 12 hour light-dark cycle with the light being onbetween 6 a.m. to 6 p.m. They were given access to powdered rat feed(Ralston Purina Rat Chow® #5012) for only 4 hours a day from 10 a.m. to2 p.m. Water was given at ad libitum. Food intake stabilized after aboutone week. On the eleventh day, the rats were divided into 4 groups of 13rats each. The groups were matched for average food intake and bodyweight, based on the means of the previous 4 days.

Three of the groups were administered the compound in Example 39. Eachgroup was assigned a specific dose. The doses were 5.6, 17.8 and 56.2milligrams per kilogram of body weight. The compound was suspended in anormal saline vehicle (of which less than 1% of it contained a 50/50mixture of propylene glycol and "TWEEN"® 80). Concentrations of thecompound were adjusted so that each rat received a volume of 2milliliter per kilograms of body weight. The fourth group received 2milliliter per kilogram of body weight of the vehicle only. The compoundand vehicle preparations were given intraperitoneal one hour before therats were given access to food.

Table 1 shows the results of the tests. A student t test was used formaking statistical comparisons, and the p-values are based upontwo-tailed comparisons.

                  TABLE 1                                                         ______________________________________                                                                          Mean Weight                                                                   Difference 24                                                                 hrs after com-                                                                pound admin-                                                    Mean Food Intake                                                                            istered Grams                               Condition     n     Grams (± S. D.)                                                                          (± S. D.)                                ______________________________________                                        Normal Saline 13    21.2 (1.2)    +2.9.sup.b (4.6)                            Compound - 5.6 mg/kg                                                                        13    17.4.sup.a (2.9)                                                                            -2.6.sup.b (3.8)                            (Ex. 39) 17.8 mg/kg                                                                         13    16.5.sup.a (4.7)                                                                            -5.2.sup.c (5.1)                               56.2 mg/kg 13    12.1.sup.a (3.0)                                                                            -9.5.sup.c (2.9)                            ______________________________________                                         .sup.a p < .002 compared with normal saline control group                     .sup.b p < .05 between pre and post weight change                             .sup.c p < .005 between pre and post weight change                       

The compound prepared in accordance with the procedure of Example 39produced a statistically significant dose responsive decrease in foodintake when compared to the normal saline control groups. The druggroups showed a statistically significant (as compared with theirprevious day's weight) dose responsive weight loss after 24 hours,whereas the normal saline group gained an average of 2.9 grams. Thecompound produced a decrease in food intake and a subsequent loss inweight.

The anorectic utility of other compounds described herein can also beshown in the following procedure.

Six groups of 12 each male Sprague Dawley derived, COBS rats fromCharles River Breeding Laboratories, (Portage, Mich.) were housed inindividual cages, maintained on a 12 hour light-dark cycle with thelight being on from 6 a.m. to 6. p.m. and given ad libitum access towater and fat feed (Ralston Purina Rat Chow® #5001). Twenty-four hoursprior to drug testing all food was removed from the cages. Groups of 12rats each were matched on the basis of body weight. Forty-five minutesbefore they were again given access to food the rats were given,intraperitoneally, either one of the five experimental compounds or itsvehicle (the control group). A single dose of 32 milligrams per kilogramof body weight of the compounds was administered. All animals receivedan injection volume of 2 milliliters per kilogram of body weight. Theamount of food consumed after two hours of access to food was measured.The mean food intake for each test compound group is presented as apercentage of its vehicle control group in Table 2.

                  TABLE 2                                                         ______________________________________                                        Compound                                                                      Described in              Food Intake %                                                                           Statistical                               Example   Dose     N      of Control                                                                              Significance                              ______________________________________                                        28        32 mg/kg 12     51%        p < .001                                 29        32 mg/kg 12     76%       p = .06                                   30        32 mg/kg 12     61%        p < .002                                 33        32 mg/kg 12     70%       p < .02                                   41        32 mg/kg 12     53%       p < .01                                   ______________________________________                                    

Each of the given compounds of the present invention produced a decreasein food intake as compared with the control group. The p-values derivedfrom statistical comparisons are presented in the last column. Only theresults of the compound from Example 29 marginally missed theconventionally acceptable p-value of p=0.05. This could indicate that asomewhat higher dose of this compound would be required for astatistically significant reduction in food intake.

Compounds of formula II are useful as intermediates for thebenzothiazine derivatives presently being disclosed and claimed.

Those skilled in the art will appreciate that the characterizingpharmacological responses to embodiments of this invention specifiedabove are intended merely for purposes of illustration and, accordingly,are not to be construed as either delimiting or exclusionary.

For therapeutic purposes, the compounds of this invention are ordinarilycombined with one or more adjuvants appropriate to the indicative routeof administration. If per os, they may be mixed with lactose, sucrose,starch powder, cellulose esters of alkanoic acids, cellulose alkylethers, talc, stearic acid, magnesium stearate, magnesium oxide, sodiumand calcium salts of phosphoric and sulfuric acids, gelatin, acacia,sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alchohol, andthus tableted or encapsulated for convenient administration;alternatively, they may be dissolved or suspended in water or acomparably innocuous liquid. Parenteral administration may be effectedvia sterile fluid and ad mixture with water, polyethylene glycol,propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesameoil, benzyl alcohol, sodium chloride and/or various buffers. Otheradjuvants and modes of administration are well and widely known in thepharmaceutical arts; see for example, F. W. Martin et. al., "Remington'sPharmaceutical Sciences," 14th edition, Merck Publishing Co., Eaton Pa.1965.

Appropriate dosages in any given instance, of course, depend upon thenature and severity of the condition treated, the route ofadministration, and the species of mammal involved, including its sizeand any individual idiosyncrasies which obtained.

Compounds of this invention when R2 is not an amino group can beprepared as follows: a 2H-1, 4-benzothiazin-3-(4H)-one of the formula##STR3## wherein R2 is hydrogen, halogen, nitro and/or alkoxy containing1 to 4 carbon atoms and, when R2 is other than alkoxy, R3 is hydrogen,when R2 is alkoxy, R3 is hydrogen or the same alkoxy, is heated in1,4-dioxane with diphosphorus pentasulfide to obtain a correspondingthione comprehended by the formula ##STR4##

Such a thione is contacted with sodium hydride in tetrahydrofuran undernitrogen, and the resultant sodio derivative is contacted in situ withiodomethane to obtain a corresponding 3-methylthio-2 H-1,4-benzothiazine comprehended by the formula ##STR5##

Such a methylthio compound is heated in N,N-dimethylformamide undernitrogen with the sodio derivative of an optionally substituted2-phenylacetonitrile prepared in situ by contacting the nitrile withsodium hydride, whereby a correspondingly optionally substituted2-phenyl-2-[2,3-dihydro-4H-1,4-benzothiazin-3-ylidene] acetonitrile isobtained which is comprehended by the formula ##STR6##

These nitriles are hydrolyzed in sulfuric acid/water solutions to affordthe corresponding amides ##STR7##

Such an amide is contacted in N,N-dimethylformamide under nitrogen witha dimethyl or diethyl ketal of the formula ##STR8## to give thecorresponding adduct ##STR9##

These adducts are converted to the corresponding tricyclic systems bytwo methods: method A, wherein intermediate compound A is treated withbis (dimethylamino) methoxy methane in DMF at 55 degrees to 60 degreesC. for 3 to 18 hours; method B, wherein the aforementioned adductsrepresented by intermediate compound A are converted to tricyclicpyrimidones by heating this adduct at 80 to 140 degrees centigrade##STR10## in DMF from 1 to 6 hours. These systems are treated with bis(dimethylamino) methoxymethane for 2 to 24 hours at 50 to 80 degreescentigrade and the resultant products ##STR11## are then heated inaqueous DMF for 2 to 18 hours to afford the desired tricyclic pyridones##STR12##

A 4-phenyl-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one of the formula##STR13## wherein R2═R3═H is contacted in N, N-dimethylformamide with aniodoalkane, in the presence of potassium carbonate to obtain acorresponding 2-alkyl-4-phenyl-5H-pyrido [3,4-b][1,4]benzothiazin-3(2H)-one comprehended by the formula ##STR14## and whichin turn is heated in N,N-dimethylformamide with an iodoalkane in thepresence of potassium carbonate to obtain a corresponding2,5-dialkyl-4-phenyl-5H-pyrido [3,4-b][1,4] benzothiazin 3(2H)-onecomprehended by the formula ##STR15##

Such a 2,5 dialkyl-4-phenyl-5H-pyrido [3,4-b][1,4]benzothiazin-3(2H)-one is contacted with ethaneperoxoic acid in aceticacid to obtain a 10-oxide comprehended by the formula ##STR16## and sucha 10-oxide or its immediate precursor is heated with ethaneperoxoic acidin acetic acid to obtain a corresponding 10,10-dioxide comprehended bythe formula ##STR17## Alternatively, a 4-phenyl-5H-pyrido [3,4-b][1,4]benzothiazin-3(2H)-one of the formula ##STR18## is (1) heated withbromine in a mixture of carbon tetrachaloride and acetic acid to obtaina corresponding 8-bromo compound comprehended by the formula ##STR19##or (2) contacted with a cold mixture of nitric and sulfuric acids toobtain a corresponding 8-nitro 10-oxide comprehended by the formula##STR20## which in turn is (1) heated with triphenylphosphine in amixture of tetrachrloromethane and acetonitrile to obtain acorresponding 10-desoxidic compound comprehended by the formula##STR21## and (2) heated with stannous chloride dihydrate in a mixtureof hydrochloric and acetic acids to obtain--upon neutralization--acorresponding 8-amino 10-desoxidic compound comprehended by the formula##STR22## Finally, an acid addition salt of the invention is obtained bycontacting--ordinarily in a solvent medium--an amino compound of thepreceding formula with an inorganic or strong organic acid such ashydrochloric, hydrobromic, hydriodic, nitric, phosphoric, sulfuric orthe methyl or ethyl ester thereof, sulfamic, benzenesulfonic,methylbenzenesulfonic, acetic, 2-hydroxy-propanoic,3-phenyl-2-propanoic, butanedioic, 2,3-dihydroxy-butanedioic,2-butenedioic, 2-hydroxy-1,2,3-pro panetricarboxylic, gluconic,ascorbic, benzoic, or the like, the relative amount of amino compoundcontacted being determined by the basicity of the acid and thestoichiometry elected where options are presented. Those substitutedphenyl acetonitriles which are appropriate for Method A may include butshould not be limited to:

p-chlorophenylacetonitrile, o-chlorophenylacetonitrile,o-fluorophenylacetonitrile, m-trifluoromethylphenyl acetonitrile,phenylacetonitrile. Those substituted phenylacetonitriles appropriatefor Method B may include but should not be limited top-bromophenylacetonitrile, p-fluorophenylacetonitrile,p-methoxyphenylacetonitrile.

Use of the appropriately substituted 2H-1, 4-benzothiazin-3-(4H)-onesuch as those halogenated at the 5, 6, or 7-position, or the 5-nitroderivative or the 6, 7-dimethoxy derivative in the previously describedsequence and various substituted phenylacetonitriles as described willproduce the desired pyridiones with this corresponding substitutionpatterns on both the fused aromatic ring and the phenyl substituent ofthe pyridone ring.

In addition use of various disubstituted phenylacetonitriles such as3,4-dichloro-or 2,6-dichloro- or 2,4-dichloro-for the monosubstitutedphenylacetonitriles in either Method A or Method B will result indisubstituted phenyl groups on the pyridone ring. The fused aromaticring of these tricycles pyridones may be unsubstituted, mono- ordisubstituted.

Throughout the foregoing preparative disclosure, R, R', R", R"', R₂, R₃,X, Y, and Z retain the meanings originally assigned.

The following examples describe in detail compounds illustrative of thepresent invention and methods which have been devised for theirpreparation. It will be apparent to those skilled in the art that manymodifications, both of materials and of methods, may be practicedwithout departing from the purpose and intent of this disclosure.Throughout the examples hereinafter set forth, temperatures are given indegrees Centigrade and relative amounts of materials in part by weight,except as otherwise noted.

EXAMPLE 1

In a one liter flask is placed 10.8 parts of prewashed sodium hydride in150 parts of N,N-dimethyl-formamide (DMF) at room temperature. Afterstirring for five minutes under nitrogen atmosphere, 30 parts of 2H-1,4-benzothiazine-3(4H)-thione [J. Med. Chem., 12, 290(1969)] is added inportions over a period of 30 minutes and continuously stirred at roomtemperature for 20 minutes. To the reaction mixture is then added 15parts of methyl iodide and the mixture stirred at room temperature for20 minutes under nitrogen. Removal of solvent by vacuum distillationunder nitrogen affords 3-methylthio-2H-1,4-benzothiazine as the residue.Since the product is subject to spontaneous hydrolytic decomposition, itis not usually isolated for the purposes of this invention but insteademployed as the solution in DMF preparable via the foregoing procedure.

EXAMPLE 2

A mixture of 12 parts 50% sodium hydride/mineral oil dispersionpreviously washed with hexane to remove the oil is suspended in 300 mlof DMF under a nitrogen atmosphere and is treated with 32 parts ofp-chlorophenylacetonitrile. After the mixture is stirred at roomtemperature for 15 minutes to 2 hours, 30 parts of3-methylthio-2H-1,4-benzothiazine from Example 1 is added to the mixtureand the reaction mixture stirred at room temperature for one hour.

The mixture is neutralized with acetic acid and diluted with one to twovolumes of water. The mixture is stirred at room temperature for 30minutes during which time the product which precipitated from thereaction mixture is filtered and dried to yield(2H-1,4-benzothiazin-3(4H)-ylidene)(4-chlorophenyl)acetonitrile meltingat approximately 137°-139°.

EXAMPLE 3

Substitution of 32 parts of o-flurophenylacetonitrile for the 32 partsof p-chlorophenylacetonitrile in Example 2 affords by the proceduretherein detailed,(2H-1,4-benzothiazin-3(4H)-ylidene)(2-fluorophenyl)acetonitrile.

EXAMPLE 4

Substitution of 32 parts of o-chlorophenylacetonitrile for 32 parts ofp-chlorophenylacetonitrile in Example 2 affords, by the proceduretherein detailed, (2H-1,4-benzothiazin-3(4H)-ylidene)(2-chlorophenyl)acetonitrile melting at about 155°-158°.

EXAMPLE 5

Substitution of 32 parts of m-trifluoromethylphenylacetonitrile for 32parts of p-chlorophenylacetonitrile called for in Example 2 affords, bythe procedure therein detailed, (2H-1,4-benzothiazin-3(4H)-ylidene[3-(trifluoromethyl)phenyl]acetonitrile melting in the range 142°-145°.

EXAMPLE 6

Substitution of 32 parts of phenylacetonitrile for 32 parts ofp-chlorophenylacetonitrile in Example 2 affords, by the proceduretherein described, (2H-1,4-benzothiazin-3(4H)-ylidene)phenylacetontrile.

EXAMPLE 7

Substitution of 32 parts of either o-methylphenylacetonitrile,m-methylphenylacetonitrile, or p-methylphenylacetonitrile for 32 partsof p-chlorophenylacetonitrile in Example 2 affords, by the proceduretherein described respectively,(2H-1,4-benzothiazin-3(4H)-ylidene)(2-methylphenyl)acetonitrile,(2H-1,4-benzothiazin-3(4H)-ylidene)(3-methylphenyl)acetonitrile and(2H-1,4-benzothiazin-3(4H)-ylidene)(4-methylphenyl) acetonitrile.

EXAMPLE 8

A mixture of 30 parts of(2H-1,4-benzothiazin-3(4H)-ylidene)(4-chlorophenyl)acetonitrile, 180parts concentrated sulfuric acid and 18 parts water is stirred at roomtemperature for 11/2 hours. The mixture is cooled to 0°-5° and dilutedwith 1 to 2 volumes of water which results in a crystalline solid whichis filtered, dried and crystallized from methanol to afford crystalline2-(2H-1,4-benzothiazin-3(4H)-ylidene)-2-(4-chlorophenyl)acetamidemelting at about 188°-191°.

EXAMPLE 9

Substitution of 30 parts of (2H-1,4-benzothiazin-3(4)-ylidene)phenylacetonitrile for 30 parts of(2H-1,4-benzothiazin-3(4H)-ylidene)(4-chlorophenyl)acetonitrile inExample 8 affords, by the procedure therein described,2-(2H-1,4-benzothiazin-3(4H)-ylidene)-2-phenylacetamide melting at about149°-151°.

EXAMPLE 10

Substitution of 30 parts of(2H-1,4-benzothiazin-3(4H)-ylidene)(2-chlorophenyl)acetonitrile for 30parts of (2H-1,4-benzothiazin-3(4H)-ylidene)(4-chlorophenyl)acetonitrilein Example 8 affords, by the procedure therein described,2-(2H-1,4-benzothiazin-3(4H)-ylidene-2-(2-chlorophenyl) acetamidemelting in the range of 167°-169°.

EXAMPLE 11

Substitution of 30 parts of(2H-1,4-benzothiazin-3(4H)-ylidene)(3-trifluoromethylphenyl)acetonitrilefor 30 parts of(2H-1,4-benzothiazin-3(4H)-ylidene)(4-chlorophenyl)acetonitrile inExample 8 affords, by the procedure therein described,2-(2H-1,4-benzothiazin-3(4H)-ylidene)-2-[3-(trifluoromethyl)phenyl]acetamidemelting in the range of 167°-168°.

EXAMPLE 12

Substitution of 30 parts of2H-1,4-benzothiazin-3(4H)ylidene)(2-fluorophenyl)acetonitrile for 30parts of (2H-1,4-benzothiazin-3(4H)-ylidene)(4 chlorophenyl)acetonitrilein Example 8 affords, by the procedure therein described,2-(2H-1,4-benzothiazin-3(4H)-ylidene-2-(2-fluorophenyl) acetamidemelting in the range of 156°-158°.

EXAMPLE 13

Substitution of 30 parts of either 2H-1,4-benzothiazin-3(4H)-ylidene(2-methylphenyl)acetonitrile, 2H-1,4-benzothiazin-3(4H)-ylidene(3-methylphenyl)acetonitrile or 2H-1,4-benzothiazin-3(4H)-ylidene(4-methylphenyl)acetonitrile in Example 8 affords, by the proceduretherein described respectively,2-(2H-1,4-benzothiazin-3(4H)-ylidene-2-(2-methylphenyl)acetamide,2-(2H-1,4-benzothiazin-3(4H)-ylidene-2-(3-methylphenyl)acetamide and2-(2H-1,4-benzothiazin-3(4H)-ylidene-2-(4 methylphenyl)acetamide.

EXAMPLE 14 (METHOD A)

In a one liter flask equipped with a magnetic stirrer are placed 35parts of2-(2H-1,4-benzothiazin-3(4H)-ylidene-2-(4-chlorophenyl)acetamide, 300parts of DMF and 20 parts of dimethylformamide diethyl acetal reagent.The mixture is stirred at room temperature overnight, and 42 parts ofmethoxy(dimethylamino)methane is then added. The mixture is heated to50° for six hours, cooled to room temperature, and poured onto about 400parts of water and stirred at room temperature. The oily semi-solidwhich formed is collected, triturated with methanol, filtered and dried.

The yellow material is further triturated with about 500 parts ofmethanol with heating then cooled, and the solid is collected, washedwith ethyl acetate followed by ether and dried. The yellow crystallinesolid is recrystallized from aqueous DMF to yield4-(4-chlorophenyl)-5H-pyrido[3,4-b][1,4] benzothiazin-3(2H)-one whichmelts above 330°.

EXAMPLE 15

Substitution of 35 parts of2-(2H-1,4-benzothiazin-3(4H)-ylidene-2-(phenyl)acetamide called for inExample 14 affords, by the procedure there detailed, 4-phenyl-5H-pyrido[3,4-b][1,4] benzothiazin-3(2H)-one melting at about 266°-271°.

EXAMPLE 16

Substitution of 35 parts of2-(2H-1,4-benzothiazin-3(4H)-ylidene-2-(2-chlorophenyl)acetamide calledfor in Example 14 affords, by the procedure there detailed,4-(2-chlorophenyl)-5H-pyrido[3,4-b][1,4] benzothiazin-3(2H)-one meltingat about 320°-323°.

EXAMPLE 17

Subsitution of 35 parts of2-(2H-1,4-benzothiazin-3(4H)-ylidene)-2-[3-(trifluoromethyl)phenyl]acetamide called for in Example 14 affords, by the procedure thereindescribed, 4-[(3-trifluoromethyl)phenyl]-5H-pyrido [3,4-b][1,4]benzothiazin-3(2H)-one melting at about 268°-270° C.

EXAMPLE 18

Substitution of 35 parts of2-(2H-1,4-benzothiazin-3(4H)-ylidene-2-(2-fluorophenyl)acetamide calledfor in Example 14 affords, by the procedure therein described,4-(2-fluorophenyl)-5H-pyrido[3,4-b][1,4] benzothiazin-3(2H)-one, whichmelts above 300°.

EXAMPLE 19

Substitution of 35 parts of either2-(2H-1,4-benzothiazin-3(4H)-ylidene-2-(2-methylphenyl) acetamide,2-(2H-1,4-benzothiazin-3(4H)-ylidene-2-(3-methylphenyl) acetamide or2-(2H-1,4-benzothiazin-3(4H)-ylidene-2-(4 methylphenyl)acetamide calledfor in Example 15 affords by the procedure therein detailed respectively4-(2-methylphenyl)-5H-pyrido [3,4-b][1,4] benzothiazin-3(2H)-one,4-(3-methylphenyl-5H-pyrido [3,4-b][1,4] benzothiazin-3(2H)-one and4-(4-methylphenyl)-pyrido [3,4-b][1,4] benzothiazin-3(2H)-one.

EXAMPLE 20

Substitution of 32 parts of p-fluorophenylacetonitrile for the 32 partsof p-chlorophenylacetonitrile in example 2 affords by the proceduretherein detailed(2H-1,4-benzothiazin-3(4H)-ylidene)(4-fluorophenyl)acetonitrile meltingat about 120°-122° C.

EXAMPLE 21

Substitution of 32 parts of p-methoxyphenylacetonitrile for the 32 partsof p-chlorophenylacetonitrile in example 2 affords by the proceduretherein described(2H-1,4-benzothiazin-3(4H)-ylidene)(4-methoxyphenyl)acetonitrile meltingat about 151°-153° C.

EXAMPLE 22

Substitution of 32 parts of p-bromophenylacetonitrile for the 32 partsof p-chlorophenylacetonitrile in example 2 affords by the proceduretherein described(2H-1,4-benzothiazin-3(4H)-ylidene)(4-bromophenyl)acetonitrile meltingat about 155°-157° C.

EXAMPLE 23

Substitution of 32 parts of either 3,4-dichlorophenylacetonitrile,2,4-dichlorophenylacetonitrile or 2,6-dichlorophenylacetonitrile inExample 2 affords by the procedure therein described respectively(2H-1,4-benzothiazin-3(4H)-ylidene)(3,4-dichlorophenyl) acetonitrile,(2H-1,4-benzothiazin-3(4H)-ylidene)(2,4-dichlorophenyl) acetonitrile, or(2H-1,4-benzothiazin-3(4H)-ylidene)(2,6-dichlorophenyl) acetonitrile.

EXAMPLE 24

Substitution of 30 parts of(2H-1,4-benzothiazin-3(4H)-ylidene)(4-fluorophenyl) acetonitrile for the30 parts of substrate of example 8 affords by the procedure thereindescribed 2-(2H-1,4-benzothiazin-3(4H)-ylidene)-2-(4-fluorophenyl)acetamide melting at about 190°-192° C.

EXAMPLE 25

Substitution of 30 parts of(2H-1,4-benzothiazin-3(4H)-ylidene)(4-methoxyphenyl) acetonitrile forthe 30 parts of substrate of Example 8 affords by the procedure thereindescribed 2-(2H-1,4-benzothiazin-3(4H)-ylidene)-2-(4-methoxyphenyl)acetamide melting at about 183°-184° C.

EXAMPLE 26

Substitution of 30 parts of(2H-1,4-benzothiazin-3(4H)-ylidene)(4-bromophenyl) acetonitrile for the30 parts of substrate of example 8 affords by the procedure thereindescribed 2-(2H-1,4-benzothiazin-3(4H)-ylidene)-2-(4-bromophenyl)acetamide melting at about 209°-210° C.

EXAMPLE 27

Substitution of 30 parts of either(2H-1,4-benzothiazin-3(4H)-ylidene)(3,4-dichlorophenyl) acetonitrile,(2H-1),4-benzothiazin-3(4H)-ylidene)(2,4-dichlorophenyl) acetonitrile,or (2H-1,4-benzothiazin-3(4H)-ylidene)(2,6-dichlorophenyl) acetonitrilefor the substrates of example 8 affords by the procedure thereindescribed respectively2-(2H-1,4-benzothiazin-3(4H)-ylidene)-2-(3,4-dichlorophenyl) acetamide,2-(2H-1,4-benzothiazin-3(4H)-ylidene)-2-(2,4-dichlorophenyl) acetamideand 2-(2H-1,4-benzothiazin-3(4H)-ylidene)-2-(2,6-dichlorophenylacetamide.

EXAMPLE 28 (Method B)

To 4 parts of 2-(2H-1,4-benzothiazin-3(4H)-ylidene)-2-(4-fluorophenyl)acetamide in 80 parts of DMF is added 6 parts dimethylformamide diethylacetal and the reaction mixture was stirred at room temperature for 2 to6 hours then heated at 80°-140° C. for 1 to 6 hours. After cooling 6parts of methoxy-bis-(dimethylamino) methane is added and the reactionmixture then heated at 50° to 80° C. for 2 to 24 hrs. The cooledreaction mixture is then diluted with 40 parts of water and refluxed for2 to 18 hr. Upon cooling the precipitate present was collected andrecrystallized from aqueous DMF to give4-(4-fluorophenyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one whichmelts above 300°.

EXAMPLE 29

Substitution of 4 parts of2-(2H-1,4-benzothiazin-3(4H)-ylidene)-2-(4-methoxyphenyl) acetamide forthe substrate in example 28 affords by the procedure therein described4-(4-methoxyphenyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)one meltingabove 300° C.

EXAMPLE 30

Substitution of 4 parts of2-(2H-1,4-benzothiazin-3(4H)-ylidene)-2-(4-bromophenyl) acetamide forthe substrate of example 28 affords by the procedure therein described4-(4-bromophenyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one meltingabove 300° C.

EXAMPLE 31

Substitution of 4 parts of either2-(2H-1,4-benzothiazin-3(4H)-ylidene)-2-(3,4-dichlorophenyl) acetamide,2-(2H-1,4-benzothiazin-3(4H)-ylidene)-2-(2,4-dichlorophenyl) acetamideor 2-(2H-1,4-benzothiazin-3(4H)-ylidene)-2-(2,6-dichlorophenyl)acetamide for the substrate of example 28 affords by the proceduretherein described respectively4-(3,4-dichlorophenyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one,4-(2,4-dichlorophenyl)-5H-[3,4-b][1,4]benzothiazin-3(2H)-one and4-(2,6-dichlorophenyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3-(2H)-one.

EXAMPLE 32

To 10 parts of4-(4-bromophenyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one suspendedin 300 parts of DMF is added 4 parts of cuprous cyanide and the reactionmixture is refluxed for 2 to 12 hours. After cooling, water is added andthe solution extracted with ethyl acetate. The combined extracts arewashed with saturated NaCl solution and dried. Solvent removal gives aresidue which upon recrystallization from aqueous DMF gives4-(4-cyanophenyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one, whichmelts above 290° C.

EXAMPLE 33

To 10 parts pyridine hydrochloride heated to 170° under a stream ofnitrogen is added 0.5 parts of4-(4-methoxyphenyl)-5H-pyrido[3,4-b][1,4]benzothiazine-3(2H)-one in oneportion. The reaction mixture is refluxed for 45 minutes, cooled, wateris added and the solid which forms is collected and dried to yield4-(4-hydroxyphenyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one, m.p.greater than 300°.

EXAMPLE 34

To 3 parts of the product of the process described in Example 14,4-(4-chlorophenyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one,suspended in 5 parts acetic acid is added and 1 part 40% peracetic acid.After ten minutes reaction time, water is added to the now homogeneousreaction mixture and the precipitate which forms is collected andrecrystallized from aqueous DMF to yield white needles of4-(4-chlorophenyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one 10 oxide,melting above 310°.

EXAMPLE 35

Substitution of the products from examples 15, 16, 17, 18, 19, 28, 29,30, 31, 32 and 33 for the4-(4-chlorophenyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one inexample 34 affords the corresponding 4-(aryl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one 10 oxide.

EXAMPLE 36

A mixture of 1 part of4-(4-chlorophenyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one, 10 partsof ethaneperoxoic acid, and 10 parts of glacial acetic acid is stirredand heated at 25° to 60° for 1 to 20 hours, whereupon insoluble solidsare filtered, washed with ethyl acetate, and dried in vacuo at 110° togive 4-(4-chlorophenyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one10,10-dioxide melting above 300°.

EXAMPLE 37

Substitution of the products from example 35 for the starting materialin example 36 will give the corresponding4-(aryl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one 10,10-dioxide.

EXAMPLE 38

Substitution of the corresponding substituted 2H-1,4benzothiazine-3(4H)-thione, derived from the appropriate2H-1,4-benzothiazin-3(4H)-ones such as the 5-chloro-derivative [J. Chem.Soc., 893 (1945)] or the 6-chloro-derivative [Can. J. Chem., 44, 1733(1965)] or the 7-chloro-derivative [Can. J. Chem., 48, 1859 (1970)] orthe 6-fluoro-derivative [J. Chem. Soc., 787 (1952) or the6-bromo-derivative [J. Chem. Soc., 2624 (1957) or the 5-nitro-derivative[Ann. Chem. (Rome) 588, 1226 (1968)] or the 6,7 dimethoxy derivative [J.Proc. Roy. Soc., N. S. Wales, 71, 112 (1938)] according to the proceduredescribed in J. Med. Chem., 12, 290 (1969), in example 1 will afford thecorresponding 3-methylthio derivatives. These in turn when substitutedin examples 2, 3, 4, 5, 6, 7, 20, 21, 22 or 23 will give thecorresponding acetonitrile derivatives. These turn when treated withaqueous sulfuric acid as described in example 8, 9, 10, 11, 12, 13, 24,25, 26, or 27 will give the corresponding acetamide derivatives. Thesein turn when treated with DMF diethyl acetal then methoxy bis(dimethylamino) methane as described in examples 14 thru 19 will givethe corresponding4-(4-chlorophenyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one or4-phenyl-5H-pyrido[3,4-b][1,4]benzothiazin-3-(2H)-one or4-(2-chlorophenyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one or4-(3-trifluoromethylphenyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-oneor 4(2-fluorophenyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one withthe respective substitution on the benzene ring. Alternatively, whenthese acetamides are treated with DMF diethyl acetal, methoxy bis(dimethylamino) methane and water as described in examples 28 thru 31,they will give the corresponding4-(4-fluorophenyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one or4-(4-methoxyphenyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one or4(4-bromophenyl)-5H-pyrido[ 3,4-b][1,4]benzothiazin-3(2H)-one with therespective substituents on the benzene ring.

EXAMPLE 39

To a solution of 1 part4-(4-chlorophenyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one in 25parts of concentrated hydrochloric acid is added 25 parts methanol. Thesolution is warmed to the mean boiling point of the alcohol. Another 50parts of methanol is added and heating continued until nearly all thesolid material is dissolved. The hot solution is filtered to removeundissolved solids and upon concentrating the solution volume offiltrate in a suction flask, yellow needles of4-(4-chlorophenyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3-ol hydrochlorideresult, melting above 300° C.

EXAMPLE 40

Substitution of the products from examples 15, 16, 17, 18, 19, 28, 29,30, 31, 32 and 33 for the4-(4-chlorophenyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H) one, inexample 39 affords the corresponding4-(aryl)-5H-pyrido[3,4-b][1,4]benzothiazin-3-ol hydrochlorides.

EXAMPLE 41

To a solution of 1 part of4-[(3-trifluoromethyl)phenyl]-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-onein 20 parts hydrochloric acid is added 60 parts methanol in 10 partsportions with swirling and heating on a steam bath. Near the boilingpoint of the alcohol, the hot solution is filtered through a scinteredglass funnel. Then the filtrate is concentrated with vacuum whilekeeping the liquid warm. After 3 portions of hydrochloric acid, theliquid is essentially finished crystallizing as short, fluffy needles.These are collected, washed, dried in air and ground using mortar andpestle to a flour consistency to yield4-[(3-trifluoromethyl)phenyl]-5H-pyrido[3,4-b][1,4]benzothiazin-3-ol,hydrochloride as a yellow powder.

EXAMPLE 42

To 0.5 parts4-(2-chlorophenyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one suspendedin 10 parts concentrated hydrochloric acid is added 10 parts methanolwhile gently warming the solution on a steam bath. A brown gum is formedand the second 10 part portion of methanol is added to substantiallysolubilize the gum. Near the boiling point of the alcohol, the solutionis filtered. The filtrate is concentrated on a steam bath using anitrogen stream. A gold precipitate formed which was air dried andpulverized to yield a bright yellow powder,4-(2-chlorophenyl)-5H-pyrido[3,4-b][1,]benzothiazin-3-ol, hydrochloride.

EXAMPLE 43

Substitution of 0.25 parts of4-(2-fluorophenyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one for the4-(2-chlorophenyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one calledfor in example 42, using 10 parts concentrated hydrochloric acid with 25parts methanol, affords by the procedure detailed therein4-(2-fluorophenyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3-ol,hydrochloride.

What is claimed is:
 1. A compound of the formula ##STR23## wherein R andR' each represent hydrogen or lower alkyl containing 1 to 4 carbonatoms; R2 and R3 represent hydrogen, halogen, nitro, amino or alkoxycontaining 1 to 4 carbon atoms; Z represents sulfur, sulfinyl orsulfonyl; Ar represents phenyl, mono or di substituted phenyl whereinthe substituents may be halogen, hydroxy, trifluoromethyl, methoxy,cyano or lower alkyl having 1 to 4 carbon atoms; and pharmaceuticallyacceptable acid addition salts thereof.
 2. A compound according to claim1 wherein R2 is hydrogen, halogen, nitro or amino and R3 is hydrogen. 3.A compound according to claim 1 wherein R2 is an alkoxy group and R3 ishydrogen or the same alkoxy group.
 4. A compound according to claim 1wherein Z is sulfinyl.
 5. A compound according to claim 1 wherein Z issulfonyl.
 6. A compound according to claim 1 wherein Z is sulfur.
 7. Acompound according to claim 6 wherein R2 and R3 are hydrogen.
 8. Acompound according to claim 7 wherein R is hydrogen.
 9. A compoundaccording to claim 7 wherein R' is hydrogen.
 10. A compound according toclaim 7 wherein R and R' are hydrogen.
 11. A compound according to claim10 wherein Ar represents phenyl.
 12. A compound according to claim 10wherein Ar represents a mono substituted phenyl wherein the substituentsare halogen.
 13. A compound according to claim 10 wherein Ar representsa mono substituted phenyl wherein the substituent is hydroxy.
 14. Acompound according to claim 10 wherein Ar represents a mono substitutedphenyl wherein the substituent is trifluoromethyl.
 15. A compoundaccording to claim 10 wherein Ar represents a mono substituted phenylwherein the substituent is methoxy.
 16. A compound according to claim 10wherein Ar represents a mono substituted phenyl wherein the substituentis cyano.
 17. A compound according to claim 10 wherein Ar represents amono substituted phenyl wherein the substituent is a lower alkyl having1 to 4 carbon atoms.
 18. A compound according to claim 10 wherein Arrepresents a di substituted phenyl.
 19. A compound according to claim 18wherein Ar represents a di substituted phenyl wherein the substituentsare halogen.
 20. A compound according to claim 12 which is4-(4-chlorophenyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one.
 21. Acompound according to claim 12 which is4-(2-chlorophenyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one.
 22. Acompound according to claim 12 which is4-(2-fluorophenyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one.
 23. Acompound according to claim 12 which is4-(4-fluorophenyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one.
 24. Acompound according to claim 12 which is4-(4-bromophenyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one.